Breast cancer is one of the leading causes of cancer mortality among Western women, and is predicted to become a leading cause of cancer death in Oriental women in countries such as Japan in the near future. The American Cancer Society estimates that 1 in 9 women face a lifetime risk of this disease, which will prove fatal for about one-quarter of those afflicted with the disease.
Tamoxifen (FIG. 1), a synthetic nonsteroidal selective estrogen receptor modulator, has been used effectively in the treatment of breast cancer for over twenty years. Tamoxifen is one of the most widely prescribed antineoplastic agents in the United States and Great Britain, and is one of the initial hormonal treatments of choice in both premenopausal and postmenopausal women with estrogen receptor positive metastatic disease. Furthermore, adjuvant therapy studies show a substantial reduction of contralateral primary breast carcinoma in tamoxifen treated women, which indicates that tamoxifen may be of use in breast cancer prevention.
Tamoxifen has tissue-specific estrogenic and antiestrogenic effects. Estrogen, an ovarian hormone, increases the risk of breast and endometrial cancer by inducing an estrogen receptor mediated increase in the frequency of breast and endometrial cell division. Cell division is essential in the complex process of genesis of human cancer since it per se increases the risk of genetic error-particularly genetic errors such as inactivation of tumor suppressor genes.
Tamoxifen has antiestrogenic effects in breast tissue. Tamoxifen's antiestrogenic effect in breast tissue is a primary mechanism by which tamoxifen inhibits the proliferation of breast cancer cells. Tamoxifen competes with estrogen for binding to cytoplasmic estrogen receptors ("ER"), with subsequent inhibition by the tamoxifen/ER complex of many of the activities of endogenous estrogen within tumor cells. Endogenous estrogen binds with ERs to promote cellular activities such as estrogen/ER-mediated gene transcription, DNA synthesis, cancer cell growth, and increases in autocrine polypeptides such as transforming growth factor-alpha, epidermal growth factor, insulin-like growth factor-II, and other growth factors that may be involved in cell proliferation. Competitive inhibition of estrogen binding to ERs by tamoxifen reduces or prevents such cancer growth inducing cellular activities. As a result of tamoxifen's antiestrogenic activity in breast tissue, tamoxifen prevents the transition of breast cancer cells from the early G1 phase to the mid-G1 phase of the cell cycle and exhibits a cytostatic effect on breast cancer cells. Tamoxifen has been shown to reduce distant breast cancer metastasis as well as local-regional recurrence of such cancers in both node-negative and node-positive women.
Tamoxifen, however, has an estrogenic effect on uterine tissues when endogenous estrogen levels are low, which occurs in postmenopausal women and oopherectimized women. Uterine epithelial cell heights are significantly increased by the estrogenic effect of tamoxifen in postmenopausal and oopherectimized women, leading to uterine hypertrophy. Tamoxifen also causes marked uterine eosinophilia. These effects have been associated with endometrial carcinoma, and long term use of tamoxifen is linked to an increased risk of endometrial cancer, up to a fivefold excess of risk relative to women not treated with tamoxifen therapy. Therefore, application of tamoxifen for long term breast cancer prevention and long term treatment of breast cancer has significant associated risks.
Efforts have been made to develop new selective estrogen receptor modulators ("SERMS") which act in a mechanism similar to that of tamoxifen in breast tissue, while avoiding the risks caused by the estrogenic effects of tamoxifen in uterine tissue. Several of these SERMS are triphenylethylene tamoxifen analogs. As shown in FIG. 2, droloxifene is a tamoxifen analog in which a 3'-hydroxyphenyl moiety is substituted in place of a phenyl moiety of tamoxifen. Droloxifene has a binding affinity for the estrogen receptor which is ten times that of tamoxifen, has been shown to have antiestrogenic activity in breast tissue and to be efficacious in treatment of advanced breast cancer, yet has lower estrogenic effects in uterus tissue than tamoxifen. Droloxifene, a New Estrogen Antagonist/Agonist, Prevents Bone Loss in Ovariectomized Rats, Ke at al., Endocrinology 136:2435-2441 (1995).
Toremifene, shown in FIG. 2, is a tamoxifen analog having a 4-chloro substituent. Pharmacologically toremifene has quite similar effects as tamoxifen on breast tissue, acting as potent antiestrogen. Toremifene also exhibits anti-tumor cytolytic effects at high doses which are independent of its antiestogenicity, effects which do not occur with high doses of tamoxifen. Antiestrogenic Potency of Toremifene and Tarnoxifen in Postmenopausal Women, Homesley et al., Am. J. Clin. Onc., 16(2):117-122 (1993).
4-Iodotamoxifen, shown in FIG. 2, is another tamoxifen analog, having a 4'-iodophenyl substituent in place of a phenyl substituent of tamoxifen. Iodination of tamoxifen at the 4'-phenyl postion reduces estrogenic activity, mimicking the high antiestrogenic activity of the tamoxifen metabolite 4'-hydroxytamoxifen, while giving the compound a longer duration of action in vivo by blocking formation of the rapidly metabolized 4'-hydroxytamoxifen metabolite. Pyrrolidino-4-iodotamoxifen and 4-Iodotamoxifen, New Analogues of the Antiestrogen Tamoxifen for the Treatment of Breast Cancer, Chander et al., Cancer Research, 51:5851-5858 (Nov. 1, 1991); Idoxifene: Report of a Phase I Study in Patients with Metastatic Breast Cancer, Coombes et al, Cancer Research, 55:1070-1074 (Mar. 1, 1995). 4-Iodotamoxifen has been shown to have less estrogenic agonist activity in uterine tissue than tamoxifen, and, therefore, is less likely to cause endometrial cancer when administered over a long term.
Idoxifene, also known as pyrrolidino-4-iodotamoxifen, shown in FIG. 2, is another tamoxifen analog, and is modeled on the 4'-iodotamoxifen analog. Idoxifene has the same general molecular structure as 4'-iodotamoxifen, except that the N,N-dimethylamino moiety of 4'-iodotamoxifen is replaced with a pyrrolidino moiety. Substitution of the pyrrolidino group for the dimethylamino group reduces possible toxic side effects by inhibiting the metabolization of the compound by the liver to a desmethyl metabolite with the concomitant release of potentially toxic formaldehyde. Idoxifene has a 2.5 to 5 fold higher affinity for ERs than tamoxifen, and is 1.5-fold more effective in inhibiting the growth of MCF-7 breast cancer cells. Idoxifene also has less uterotrophic estogenic effects than tamoxifen and 4'-iodotamoxifen, and produced uterotrophic effects comparable to that of tamoxifen only at a dose which was ten times greater. Pyrrrolidino4-Iodotamoxifen and 4-Iodotamoxifen, New Analogues of the Antiestrogen Tamoxifen for the Treatment of Breast Cancer, Chander et al., Cancer Research, 51:5851-5858 (November 1991); Idoxifene: Report of a Phase I Study in Patients with Metastatic Breast Cancer, Coombes et al., Cancer Research, 55:1070-1074 (Mar. 1, 1995).
Other SERMS which are not tamoxifen analogs have shown effectiveness in preventing or minimizing the development of breast cancer. Raloxifene (FIG. 3), a benzothiophene derivative, has shown potent antiestrogenic inhibition of estradiol binding to the ER and significantly inhibits estrogen dependent proliferation of MCF-7 cells derived from human mammary tissue. Raloxifene, unlike tamoxifen and its analogs, exhibits an antiestrogenic effect in uterine tissue, and provides a nearly complete blockade of uterotrophic responses to estrogen as well as tamoxifen. Selective Estrogen Receptor Modulators, Kauffman & Bryant, DN&P, 8(9) 531-539 (November 1995).
It is desirable to utilize these SERMS to develop new compositions which may be used to improve the SERMS' prevention or minimization of the development of breast cancer while reducing their uterotrophic activity, if any.